2. Academic Validation
  3. Combination of Antiviral Drugs to Inhibit SARS-CoV-2 Polymerase and Exonuclease as Potential COVID-19 Therapeutics

Combination of Antiviral Drugs to Inhibit SARS-CoV-2 Polymerase and Exonuclease as Potential COVID-19 Therapeutics

  • bioRxiv. 2021 Jul 21:2021.07.21.453274. doi: 10.1101/2021.07.21.453274.
Xuanting Wang 1 2,  Carolina Q Sacramento 3 4,  Steffen Jockusch 1 5,  Otávio Augusto Chaves 3 4,  Chuanjuan Tao 1 2,  Natalia Fintelman-Rodrigues 3 4,  Minchen Chien 1 2,  Jairo R Temerozo 6 7,  Xiaoxu Li 1 2,  Shiv Kumar 1 2,  Wei Xie 8,  Dinshaw J Patel 8,  Cindy Meyer 9,  Aitor Garzia 9,  Thomas Tuschl 9,  Patrícia T Bozza 3,  James J Russo 1 2,  Thiago Moreno L Souza 3 4,  Jingyue Ju 1 2 10
Affiliations

Affiliations

  • 1 Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027.
  • 2 Department of Chemical Engineering, Columbia University, New York, NY 10027.
  • 3 Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil.
  • 4 National Institute for Science and Technology for Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil.
  • 5 Department of Chemistry, Columbia University, New York, NY 10027.
  • 6 Laboratory on Thymus Research, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil.
  • 7 National Institute for Science and Technology on Neuroimmunomodulation (INCT/NIM), Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil.
  • 8 Laboratory of Structural Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
  • 9 Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY 10065.
  • 10 Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY 10032.
PMID: 34312622 DOI: 10.1101/2021.07.21.453274
Abstract

SARS-CoV-2 has an exonuclease-based proofreader, which removes nucleotide inhibitors such as Remdesivir that are incorporated into the viral RNA during replication, reducing the efficacy of these drugs for treating COVID-19. Combinations of inhibitors of both the viral RNA-dependent RNA polymerase and the exonuclease could overcome this deficiency. Here we report the identification of hepatitis C virus NS5A inhibitors Pibrentasvir and Ombitasvir as SARS-CoV-2 exonuclease inhibitors. In the presence of Pibrentasvir, RNAs terminated with the active forms of the prodrugs Sofosbuvir, Remdesivir, Favipiravir, Molnupiravir and AT-527 were largely protected from excision by the exonuclease, while in the absence of Pibrentasvir, there was rapid excision. Due to its unique structure, Tenofovir-terminated RNA was highly resistant to exonuclease excision even in the absence of Pibrentasvir. Viral Cell Culture studies also demonstrate significant synergy using this combination strategy. This study supports the use of combination drugs that inhibit both the SARS-CoV-2 polymerase and exonuclease for effective COVID-19 treatment.

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